The endothelium synthesizes and releases paracrine hormones that regulate the contraction of vascular smooth muscle cells. In addition to the well- described vasorelaxant factors recent experiments indicate that the endothelium also releases vasoconstrictor compounds (e.g., endothelin). The objective of this investigation is to study the role on endothelin in the modulation of fetoplacental vascular resistance in humans and to study its potential role in high-risk pregnancies associated with maternal hypertension and decreased fetoplacental blood flow. The vasoconstrictor action of endothelin is dependent on its local concentration, the presence of specific high affinity receptor sites, and post-receptor coupling to effector mechanisms to cause vasoconstriction. We will compare endothelin production, binding sites, vascular responsiveness and endothelin- stimulated eicosanoid production in placentas from normal pregnancies with placentas from high-risk pregnancies due to pregnancy-induced hypertension, essential hypertension, intrauterine growth retardation and diabetes mellitus. Endothelin-1, endothelin-2, endothelin-3 and endothelin (1-38) will be measured using sensitive and specific assays which combine extraction, HPLC fractionation and radioimmunoassay. The dually perfused isolated placental cotyledon will be used to study endothelin production, vascular responsiveness to endothelin and the relationship between endothelin and eicosanoids. Endothelin receptor sites will be characterized using ligand binding techniques in a membrane fraction prepared from placental vessels. These experiments will provide important new information on the production and actions of endothelin in human pregnancy and provide insights critical to our understanding of the pathogenesis of vasoconstriction in high-risk pregnancies.